Temporal lobe epilepsy (TLE) is the most common of the acquired epilepsies and is characterized by an initial injury that eventually leads to the development of chronic seizures, during a process known as epileptogenesis. It is known that mitochondrial dysfunction and increased levels of reactive oxygen species contribute to enhanced neuronal excitability during the development of chronic seizures. However, the etiology of the metabolic dysfunction and oxidative stress are unknown. A potential unifying mechanism linking these bioenergetic and redox changes in the development of epilepsy is dysregulation of sirtuin 3 (SIRT3). This proposal will investigate 1) the loss of the activity of SIRT3 and its substrates during epileptogenesis as a result of aberrant mitochondrial hyperacetylation, 2) the potential efficacy of SIRT3 activation on attenuating the development of chronic epilepsy by restoring metabolic and mitochondrial homeostasis, and 3) the effects of neuronal deletion of SIRT3 on epilepsy development and impairments in mitochondrial bioenergetics. These studies will utilize novel metabolic and neuronal techniques to assess multiple parameters of neurometabolism in epilepsy models. Further, this proposal will investigate an innovative therapy to reduce or prevent the progression of epileptogenesis. The results from the proposed studies will provide novel insight into the mechanisms underlying the development of chronic epilepsy and may lead to the development of new therapies to attenuate the progression of this neurodegenerative disease.